Non-cytotoxic release of lysosomal enzymes from polymorphonuclear leukocytes (PMNs) may mediate lung inflammation in hypersensitivity vasculitis, shock lung, and emphysema. We will test the possibility that protease inhibitors, appropriately presented to PMN by encapsulating the inhibitors in immunoglobulin-coated liposomes, will modify damage to lung vasculature in vitro by lysosomal proteases. Some soluble or particulate immune reactants (C5a, aggregated IgG, Sepharose-IgG, Sepharose-3b, endotoxin) provoke the exocytosis of the contents of both azurophile and specific granules of PMNs; others (phorbol myristate acetate, concanavalin A) the release only of specific granule contents. After determining which stimuli provoke the release of known human PMN proteases (cathepsin D, cathepsin G, collagenase, elastase) we will assess, by means of inhibitors (e.g., delta-I antitrypsin, pepstatin, phosphoramidon, elastatinal), which of these enzymes are most likely responsible for vessel injury. Inhibitors will be tested for their capacity to protect isolated vessel strips, endothelial cell cultures, and lung gragments from injury (assessed biochemically and ultrastructurally) induced by PMN secretions and purified enzymes. These inhibitors will be presented in two ways: either dissolved in the fluid medium around PMNs and/or the purified proteases or as encapsulated in IgG-coated liposomes fed to PMNs before these cells are permitted to secrete proteases upon immune stimulation. Finally, we will determine whether IgG-coated liposomes bearing protease inhibitors can be taken up by PMNs in vitro and in vivo, subsequently to inhibit PMN-dependent lung injury. These studies should permit a rational approach to PMN-dependent lung inflammation and lead to therapeutic intervention in genetic deficiencies of protease inhibitors.